Considerable evidence indicates that hypoxia has lasting effects on ventilation that persist long after termination of the exposure. Although some evidence also exists that changes in sympathetic nervous system activity (SNA) persist after hypoxic exposure, the time domains of these changes and the mechanisms that underlie these alterations of SNA are poorly defined. In this proposal, we intend to better define the time course and the mechanisms of the SNA response following hypoxia in normal human volunteers. Our preliminary data suggest that: 1) brief hypoxic exposures (20 min to 2 hours) result in postexposure sustained sympathoexcitation despite producing no change in chemosensitivity; and, 2) intermediate duration hypoxic exposures (8 hours) result in sympathoinhibition despite apparently increased chemosensitivity. Based on these and other findings, and recognizing the crucial modulatory role of baro and chemoreflexes on SNA, we have formulated three hypotheses. First, we hypothesize that brief exposures to hypoxia produce sustained sympathoexcitation primarily through engagement of arterial baroreflex mechanisms. Second, we hypothesize that intermediate exposure to hypoxia produces sympathoinhibition because baroreflex stimulation occurs as arterial pressure increases and incomplete ventilatory acclimatization fails to counter the decrease in SNA. Finally, we hypothesize that long-term hypoxic exposure produces sustained sympathoexcitation in humans primarily through chemoreflex, rather than baroreflex, mechanisms. We will test these hypotheses in a series of investigations designed to test the role of baroreflexes and peripheral chemoreflexes in the alterations of SNA following hypoxic exposures of varying durations. We will use intra-arterial a-receptor blockade to test for sustained vasodilation and we will use phenylephrine and nitroprusside to assess baroreflex sensitivity. We will use hyperoxia and progressive isocapnic hypoxia to assess chemoreflex activation. In all studies we will use peroneal microneurography and catecholamine measurements to quantify SNA. By further characterizing the time domains and the mechanisms of SNA after hypoxic exposure, these studies will have implications for normal physiology (altitude acclimatization) and for pathophysiology (obstructive sleep apnea).